title: Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism.
abstract: Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Golan
authors.initials: G
authors.lastname: Karvat
authors.affiliation: Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Kimchi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001321:Autistic Disorder / Q000150:complications* / Q000235:genetics; D002421:Caudate Nucleus / Q000187:drug effects / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000077265:Donepezil; D004333:Drug Administration Routes; D005106:Exploratory Behavior / Q000187:drug effects; D007189:Indans / Q000627:therapeutic use; D007398:Interpersonal Relations; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D010880:Piperidines / Q000627:therapeutic use; D012920:Social Behavior Disorders / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D013239:Stereotyped Behavior
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D000109:Acetylcholine